Department of Urology, Northern Jiangsu People's Hospital, Yangzhou, China.
Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, China.
Sci Rep. 2024 Aug 6;14(1):18254. doi: 10.1038/s41598-024-69183-z.
The efficacy of immunotherapy for clear cell renal cell carcinoma (ccRCC), especially advanced ccRCC, is limited, presenting a clinical challenge. This limitation is closely tied to the immune regulation network. Understanding the heterogeneity of the tumour microenvironment (TME) is crucial for developing advanced ccRCC therapies. Using publicly available ccRCC data (scRNA-seq, bulk RNA-seq, and somatic mutation data), a multiomics study was performed to explore TME heterogeneity. Three distinct ccRCC immune subtypes were identified through combined scRNA-seq and bulk RNA-seq analysis. A prognostic model based on unique cell signalling molecules in immunosuppressive tumour subtype was validated in the TCGA and CheckMate cohorts. MDK emerged as a critical regulatory gene in the immunosuppressive subtype, predicting a poor ccRCC prognosis and a poor immunotherapy response. MDK promotes M2 macrophage polarization via the MDK-LRP1 interaction, and the inhibition of MDK suppressed M2 polarization. This study revealed the heterogeneity of the ccRCC TME and a reliable prognostic model, shedding light on the vital role of MDK in the immunosuppressive TME and paving the way for optimized ccRCC immunotherapy.
免疫疗法治疗透明细胞肾细胞癌（ccRCC），尤其是晚期 ccRCC，疗效有限，这是一个临床挑战。这种局限性与免疫调节网络密切相关。了解肿瘤微环境（TME）的异质性对于开发先进的 ccRCC 治疗方法至关重要。本研究使用公开的 ccRCC 数据（scRNA-seq、bulk RNA-seq 和体细胞突变数据），通过多组学研究探索 TME 异质性。通过联合 scRNA-seq 和 bulk RNA-seq 分析，确定了三种不同的 ccRCC 免疫亚型。在 TCGA 和 CheckMate 队列中验证了基于免疫抑制性肿瘤亚型独特细胞信号分子的预后模型。MDK 作为免疫抑制亚型中的关键调节基因出现，可预测 ccRCC 预后不良和免疫治疗反应不良。MDK 通过 MDK-LRP1 相互作用促进 M2 巨噬细胞极化，抑制 MDK 可抑制 M2 极化。本研究揭示了 ccRCC TME 的异质性和可靠的预后模型，阐明了 MDK 在免疫抑制性 TME 中的重要作用，为优化 ccRCC 免疫治疗铺平了道路。
